The Rising Incidence of Isoniazid Resistance: Its Clinical Significance * JACK REISS, M.D., F.C.C.P.·· and SAM M. TOWNSEND, M.S.t Coral Gables, Florida
With the advent of streptomycin in the treatment of pulmonary tuberculosis, it soon became evident that tubercle bacilli become resistant to the drug. This was particularly true in patients with cavitary disease. There was great concern among phthisiologists that the spread of streptomycin resistant tubercle bacilli might become a serious public health problem. Studies were soon begun, testing the drug susceptibility of tubercle bacilli recovered from patients. l , 2, 3, 4, 5 When para-aminosalicylic acid (PAS) and isoniazid (INH) became available, it was soon noted that combinations of the drugs prolonged the period when the bacilli become resistant to streptomycin (SM). At the Veterans Administration Hospital, Coral Gables, Florida, isoniazid sensitivity tests were performed on 322 consecutive patients of whom 133 had positive cultures from more than one specimen. Thirty- . three (10 per cent) were resistant to 5 meg. cc. of INH on the initial positive growth. None of the latter group had prior treatment with isoniazid as far as could be ascertained. Twenty-five had far-advanced and eight had moderately advanced disease. An analysis of the 33 who were resistant to isonicotinic acid hydrazide at the start of therapy revealed that practically all with newly discovered disease with one exception (15 out of 16) became negative and arrested their disease in spite of initial resistance to isoniazid. These patients received combined drug treatment according to the Veterans Administration protocol. Ten received isoniazid (INH) plus streptomycin (SM) or isoniazid plus para-aminosalicylic acid (PAS), and six SM plus PAS. The remainder of this group of 33 patients consisted of 17 with chronic cavitary disease, mostly of long duration (5 to 25 years). Only eight of this group became negative on chemotherapy, five were arrested, and three left against medical advice at a point when the sputa were negative. Nine remained problems of therapy. Patients with chronic cavitary disease may respond well to isoniazid for various intervals, in spite of initial resistance; however, the majority of them require a surgical procedure at the proper time to arrest their disease. Experimentally the correlation between emergence of resistance to isoniazid and attenuation for guinea pigs is good," 7 Might not the same process occur in human beings, giving the host an opportunity to counterFrom the Medical Service and Research Laboratories, Veterans Administration Hospital. ·Presented at Annual Conference, Florida Tuberculosis and Health Association, April 13-14, 1956. • • Chief, Pulmonary Disease Section, Medical Service.
act his infection? Two cases are presented to illustrate that primary resistance to INH in vitro does not necessarily indicate a poor clinical response. Case Reports Case 1: R. H., Sr., a 30 year old colored laborer, was admitted on Jan. 1, 1953, with history of productive cough for one year, fever, and loss of weight of thirty days duration. There is a history of chronic alcoholism and anti-luetic therapy in the service. He was acutely ill on admission and was started on 300 mg. of INH daily and SM gm, I, twice weekly. X-ray films on admission (Fig. 1) revealed evidence of disease, involving the entire right lung with a 2~ em. cavity in the apex. There was also disease, involving the upper half of the left lung. Sputums were positive and original culture was resistant to all concentrations (6 mcg./cc. of INH). Sputum cultures one month and two months after start of therapy were resistant to all concentrations of INH and all concentrations of SM (100 mcg./cc.). Sputums became negative by smear and culture three months after start of therapy and remained negative until November 28, 1963, when he went AWOL. His final x-ray (Fig. 2) showed almost complete resolution of the pulmonary infiltrations and atelectasis of the right upper lobe. This veteran was infected with tubercle bacilli which were initially resistant to INH and soon became resistant to SM in addition. His sputum converted and he showed an excellent clinical and radiological response. Follow up film three years later (Fig. 3) reveals atelectasis right upper lobe. He is working and has remained well. CCUJ6 !: A. M., a 26 year old colored truck driver, was admitted to the hospital January 5, 1963, with a five month history of weakness, malaise, loose watery stools, cough, poor appetite and loss of 26 pounds. He was acutely ill. X-ray films revealed extensive bilateral pulmonary involvement with a large cyst in the upper lobe with honeycombing in the lower portion of the left upper lobe and exudative infiltration of upper two-thirds of the right lung (Fig. 4). Sputums were positive for tuberculosis and initial culture revealed organisms resistant to all concentrations of INH. He was started on 100 mg. of INH t.i.d, daily and SM gm. I, twice weekly. After two months of therapy, the organisms were still resistant to INH and in addition to SM in all dilution (5 mcg./cc. INH and 100 mcg./cc. of SM). Sputum became negative by smear and culture four and a half months after institution of treatment and remained negative until discharge. Pneumoperitoneum was started February 12, 1963. X-ray film (Fig. 6) just prior to surgery revealed fluid level in large cyst in left upper lobe. On November 17, 1953, left upper lobectomy was performed, a thoracoplasty, and decortication of the left lower lobe. He had a stormy postoperative course but recovered. On February 16, 1964, he left the hospital AWOL. (Sputums were negative by smear and culture for seven months). X-ray film (Fig. 6), following left upper lobectomy and thoracoplasty. His sputum converted and he showed considerable x-ray film and clinical improvement on the two drugs to which he was resistant; however, surgical intervention was required to bring him to an inactive status.
Discussion Resistance to drugs in vitro does not necessarily indicate resistance in vivo. The period during which isoniazid remains effective in patients is still to be determined. On the basis of this small series of cases no definite conclusions can be drawn. However, there seems to be a rising incidence of primary resistance to isoniazid in patients on admission to this hospital. The Veterans Administration" has reported (20 hospitals reporting) an incidence of 9.8 per cent initial resistance to 1 and 5 mcg.z'cc, of INH. Meyer and Durand report an incidence of 8.03 per cent of primary resistance to 5 meg, of INH.9 The problem of possible attenuation of isoniazid-resistant tubercle bacilli for human beings is a complex one; however, this study indicates that isoniazid resistance may not have the fearful connotation connected with resistance to streptomycin and paraaminosalicylic acid.
Figure 1 (Case 1): Admission x-ray film reveals exudative lesion, involving the entire right lung with a 2~ cm. cavity in the apex and an exudative lesion involving upper half of the left lung.-Figure f (Case 1) : X-ray film prior to discharge reveals complete resolution of the pulmonary infiltrations and atelectasis of the right upper lobe.-Figure 3 (Case 1): Follow up film three years later reveals atelectasis of right upper lobe.
(Case 2): X-ray film following left upper lobe lobectomy and thoracoplasty.
FigurfJ 4 (Case 2): Admission x-ray film reveals extensive bilateral pulmonary involvement with a large cystic cavity in the left upper lobe, honeycombing in the lower portion of the left upper lobe and infiltration of upper two-thirds of the right lung.-FiI1UTfJ 5 (Case 2) : Left lateral x-ray film just prior to surgery shows fluid level in the large cystic cavity in the left upper 10be.-Fil1urfJ 6
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REISS AND TOWNSEND
1. In a series of 322 consecutive patients, an incidence of primary resistance to isoniazid of 10 per cent was demonstrated. 2. Newly diagnosed cases of pulmonary tuberculosis respond well to combined drug regime in spite of initial resistance to isoniazid. 3. Patients with chronic cavitary tuberculosis of long duration who are initially resistant to INH may respond well to combined chemotherapy; however, most of them require surgical help to effect an arrest of their disease. 4. Drug resistance has thus far not become a public health problem in newly discovered untreated patients. RESUMEN
1. Se demostro la frecuencia de la resistencia primaria a la isoniacida en diez por ciento de 322 enfermos en serie consecutiva. 2. A pesar de la resistencia inicial a Ia isoniacida los nuevos casos de tuberculosis responden bien a los regimenes de drogas combinadas. 3. Los enfermos con tuberculosis cavitaria cronica de larga duraci6n que inicialmente son resistentes a la isoniacida pueden responder bien a la drogoterapia combinada; sin embargo, Ia mayoria de ellos requieren de la cirugia para obtener la detencion de su enfermedad. 4. La resistencia a las drogas hasta ahora, no se ha constituido en un problema de salubridad publica en los nuevos casos descubiertos sintratamiento, RESUME
1. Sur un groupe de 322 malades, les auteurs ont pu deceler 10% de resistance a I'isoniazide avant tout traitement. 2. Les cas de tuberculose pulmonaire precocement diagnostiques repondent bien au traitement par l'association medicamenteuse malgre Ie resistance initiale a l'isoniazide. 3. Les malades atteints depuis longtemps de tuberculose cavitaire, qui sont d'emblee resistants a l'isoniazide, peuvent repondre favorablement au traitement chimiotherapique combine; toutefois la plupart d'entre eux ont besoin d'un complement chirurgical pour obtenir la stabilisation de leur affection. 4. La resistance a la chimiotherapie n'est pas devenue un problema sanitaire chez les malades decouverte recemment, et qui n'ont pas encore ete traites. ZUSAMMENFASSUNG
1. In einer Reihe von 322 aufeinander folgenden Kranken wurde ein Vorkommen einer primaren Resistenz gegen INH in 10% nachgewiesen. 2. Frisch erkannte FaIle von Lungentuberkulose reagieren gUnstig auf eine kombinierte medikamentose Verordnung trotz initialer Resistenz gegen INH. 3. Kranke mit chronischer cavititer langdauernder Tuberkulose, die anfanglich resistent gegen INH sind, konnen giinstig auf kombinierte Chemo-
Therapie reagieren; die meisten von ihnen benotigen jedoch chirurgische Hilfe, damit es zu einem Stillstand ihrer Erkrankung kommt. 4. ArzneimitteI-Resistenz hat sich somit nicht zu einem Problem der offentlichen Gesundheitsfiirsorge entwickelt in den Fallen von frisch entdeckten unbehandelten Patienten. REFERENCES 1 Furtos, N. D. and Doane, E. A.: "Transmission of Streptomycin Resistant Tubercle Bacilli in Man," J.A.M.A., 140:1274, 1949. 2 Brennan, A. J. and Wichelhausen, R. H.: "Streptomycin-Resistant Tubercle Bacilli," J.A.M.A., 140:1275, 1949. 3 Thomas, O. F., Borthwick, W. M., Horne, N. W. and Crofton, J. W.: "Infection with Drug-Resistant Tubercle Bacilli," Lancet, 1: 1308, 1954. 4 Cummings, M. M. and Livings, D. G.: "The Prevalence of Streptomycin-Resistant Tubercle Bacilli Among 5,526 Patients Admitted to Hospitals," Am. Rev. Tubere., 70:637, 1954. 5 Editorial: "Streptomycin-Resistant Tubercle Bacilli as a Public Health Hazard," New England J. Med., 251 :584, 1954. 6 Peizer, L. R., Minkin, A. and Wideloch, D.: "A Further Study of Virulence in Guinea Pigs of Isoniazid Resistant Tubercle Bacilli Isolated from Clinical Material," Am. Rev. Tuberc., 70:728, 1954. 7 Conalty, M. L. and Gaffney, E. E.: "Studies on Izoniazid-Resistant Strains of Mycobacterium Tuberculosis," Am. Rev. Tub ere., 71 :799, 1955. 8 Dye, W. E.: Bacteriologist: Personal Communication, Oteen, N. C. 9 Meyer, L. and Durand, M.: "Rising Incidence of Isoniazid Resistance in Patients on Admission to the Sanatorium," Rev. de la tuberc., 18 :740, 1954. (Abstract in Am. Rev. of Tuberc., 71 :128, 1955.) 10 Oestreicher, R., Dressler, S. H., Russel, W. F., Jr., Grow, J. B. and Middlebrook, G.: Ob8eMJations on the Pathogenicity of Isoniazid Resistant Mutants of Tubercle Bacilli for Tuberculous Patiente. Trans. 14th Conf. Chem. of T. B., VA Army, Navy, 207, 1955.